DESCRIPTION: The conducting respiratory epithelium is a target for immune-mediated damage in many lung diseases, such as acute lung injury, viral infection, autoimmune disease, and interstitial lung disease. T cells induce apoptosis of lung epithelial cells by release of cytokines and activation of apoptotic pathways. One of the apoptotic pathways utilized by T cells involves Fas/APO-1, which is transmembrane receptor member of the tumor necrosis factor superfamily. Cytokines such as IFN-gamma (IFN) can cooperate with the Fas pathway to enhance elimination of damaged lung epithelial cells, but excessive apoptosis can lead to chronic immune activation and lung fibrosis. Preliminary data show that IFN alone and in cooperation with Fas induces apoptosis in lung epithelial cell lines. In addition, activation of the Fas pathway in lung epithelial cells activates specific caspases, previously known as cysteine proteases, that induce cleavage of focal adhesion kinase (FAK). Dexamethasone, widely used as a treatment for inflammatory lung diseases, is a potent inhibitor of IFN and FAS-mediated cell death. The specific role of IFN in FAS-mediated apoptosis of lung epithelial cells, and how dexamethasone inhibit this process, however, is unknown. The goal of this proposal is to describe th Fas pathway in lung epithelial cell lines. To accomplish this, the specific aims are: 1) to characterize the role of caspase-mediated cleavage of FAK during Fas-triggered apoptosis in lung epithelial cells; 2) to characterize th mechanism by which IFN induces apoptosis in lung epithelial cells and sensitizes the cells to Fas-mediated apoptosis; and 3) to characterize the rol of hIAP-1 as a mediator of glucocorticoid-induced inhibition of apoptosis in lung epithelial cells. Taken together these studies will reveal the functional significance of FAK cleavage in lung epithelial cell apoptosis, how IFN induce apoptosis and sensitizes lung epithelial cells to Fas-mediated apoptosis, and how dexamethasone blocks activation of the Fas signaling pathway.